Abstract B026: SNX-2112 interferes with mitochondrial metabolism in TP53 mutant tumors

Abstract

Abstract Introduction: SNX-5422 is an orally active prodrug of SNX-2112, a potent, highly selective inhibitor of Hsp90 with epigenetic character that has shown antitumor activity in clinical trials. K562 cells have loss of p53 expression by nonsense-mediated mRNA decay. Since both loss of function TP53 mutations and MYC-driven tumors have been linked to aberrant cancer metabolism, including increased glycolysis, the effect of SNX-2112 on oncometabolic networks in the TP53 mutant chronic myelocytic leukemia K562 cell line was examined. Methods: The 50% inhibition concentration (IC50) of SNX-2112 on cell viability of cancer cell lines was determined using CellTiter-Glo® Luminescent Cell Viability Assay after incubation at various concentrations. All cells were cultured in media supplemented with 10% fetal bovine serum at 37°C, 5% CO2 and 95% humidity. Culture medium was purchased from GIBCO or Sigma, USA. Data from transcriptomics of the K562 cell line treated with SNX-2112 were obtained, and affected genes were analyzed for their roles in metabolic processes. Results: The IC50 values in TP53 null and in MYC-rearranged tumor cell lines obtained are shown in the table. Transcriptomics analysis of the effect of SNX-2112 on K562 onco-metabolism revealed that several genes involved in glycolysis (including AK2 and PCK2) and in the tricarboxylic cycle (e.g., DLST) were downregulated. SNX-2112 impaired the catabolism of branched-chain amino acids, as indicated by downregulation of BCAT, for example. Reductions were also observed in the following: ribosomal genes (MRPLs, MRPSs) associated with RNA translation; regulators of purine biosynthesis/one-carbon cycle (e.g., MTHFD1); and effectors of oxidative phosphorylation, including CYC1 and CYCS. Mitochondrial genes participating in carbohydrate (e.g., MECR, AUH) and protein metabolisms (MIPEP, SCO2), as well as redox and detoxification (e.g., SOD2, SUOX) pathways were downregulated. Conclusion: SNX-2112 demonstrated significant antitumor activity in TP53 null tumors and in rearranged MYC (8q24) hematologic and selected solid tumors (e.g., hepatocellular carcinoma, mesothelioma). This activity appears to be, in part, the result of interference with onco-metabolic pathways. Further research into this mechanism is ongoing to support this target in clinical trials. Cell LineTumor TypeIC50 (nM)TP53 null cell linesHep3BHepatocellular carcinoma7KATO IIIGastric carcinoma12NCI-H1299NSCLC - Adenocarcinoma8NCI-H358NSCLC - Adenocarcinoma10HL-60Acute promyelocytic leukemia31SK-MES-1NSCLC - SQCC10MEC-1Chronic lymphocytic leukemia5NCI-H520NSCLC - SQCC18RERF-LC-AINSCLC - SQCC54MYC-rearranged cell linesNAMALWABurkitt lymphoma4ST486Burkitt lymphoma4DaudiBurkitt lymphoma6RajiBurkitt lymphoma8CA46Burkitt lymphoma14SU-DHL-6DLBCL GCB - Double hit lymphoma6DOHH-2DLBCL GCB - Double hit lymphoma2WSU-DLCL-2DLBCL GCB - Richter’s FCL4NB-4Acute promyelocytic leukemia6AMO-1Multiple myeloma6MsTo 211HMesothelioma9NCI-H2452Mesothelioma7 Citation Format: Everardus Orlemans. SNX-2112 interferes with mitochondrial metabolism in TP53 mutant tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B026.